A human skin is roughly classified into three layers of epidermis, dermis and subcutaneous tissue, and epidermis and dermis are contacted each other through a basement membrane.
An epidermic cell contacting with the basement membrane repeats division without cease, and the divided epidermic cells are successively pushed upward to form stratum comeum, which is the uppermost layer of epidermis, via differentiation. Stratum corneum is an extremely important site from a viewpoint of beauty. Since the basement membrane structure has great influence on division of epidermic cells, it can be said that the basement membrane also has great influence on a skin.
The basement membrane is one of extracellular matrices, and is composed of type IV collagen, proteoglycan, laminin, fibronectin and the like.
An extracellular space in dermis is filled mainly with a network structure of a huge macromolecule called extracellular matrix (ECM). The ECM is composed of fibrous proteins such as collagen, elastin, fibronectin, laminin and the like, and polysaccharides called glycosaminoglycan or proteoglycan. Due to such the structure, dermis has great influence on elasticity and tension of a skin.
Up to now, it has been known that ultraviolet ray is greatly involved in changes of a skin accompanied with aging, that are, wrinkles, dullness, lost of texture, reduction in elasticity and the like. When these changes are observed microscopically, in dermis, ECM components such as collagen, elastin and the like are reduced and denatured and, further, damage of a basement membrane and thickening of epidermis occur.
With progress of recent study, as a factor inducing these changes, in particular, involvement of matrix metalloproteases (MMPs) is pointed out. MMPs is a generic name of a group of metalloproteases which main substrate is an extracellular matrix protein. Many kinds of MMPs are known, and they have common structural or functional characteristics, but their substrate proteins are different from each other (Kaori Miyazaki et al. “Biochemistry”, vol. 68, No. 12, pp. 1791–1807 (1996)).
MMPs are usually classified into collagenase group, gelatinase group, stromlycin group, and others (matrilycin etc.) in view of their structures and functions.
The collagenase group includes MMP-1 (interstitial collagenase), MMP-8, MMP-13 and the like. Inter alia, MMP-1 is known to be an enzyme degrading type I collagen, type III collagen and the like, which are main components of dermis matrix. Also, MMP-8 and MMP-13 have the action of degrading type I collagen and the like.
The gelatinase group includes MMP-2, MMP-9 and the like. MMP-2 and MMP-9 are known to be an enzyme degrading type IV collagen and laminin which are basement membrane components, and degrading elastin and the like which are dermis matrix components.
The stromlycin group includes MMP-3, MMP-10 and the like. MMP-3 and MMP-10 are known to be an enzyme degrading proteoglycan, type IV collagen, laminin and the like.
Also, expressions of these respective enzymes are greatly increased by irradiation of ultraviolet ray, which becomes one cause of reduction and denaturation in ECM by ultraviolet ray. This is thought to be one great factor for wrinkle-formation and the like on a skin (Gary J. Fisher et al., “Nature”, 379 (25), 335(1996); Gary J. Fisher et al, “The New England Journal of Medicine”, 337(20), 1419(1997)).
Therefore, it is considered that inhibition of MMPs activity is important in protecting the basement membrane and various extracellular matrices, and improving or preventing skin aging such as wrinkles and slacks. Thus, excellent MMPs inhibiting substances are desired.
In addition, since MMPs are involved in tissue matrix degradation as described above, it is suggested that MMPs are involved in many disease states accompanying abnormal metabolism of a connecting tissue or a basement membrane matrix, for example, arthritis (rheumatoid arthritis, osteoarthritis etc.), bone disease (osteoporosis etc.), periodontal disease, ectopic angiogenesis, multiple sclerosis, metastasis of tumor, and tissue ulcer formation (ulcer formation of cornea, epidermis, stomach etc.) (WO 98/08815 etc.). Therefore, MMPs inhibitor is also expected as an agent for treating or preventing these diseases due to abnormal metabolism of tissue matrix.